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Lack of pharmacokinetic drug–drug interaction between ramucirumab and irinotecan in patients with advanced solid tumors

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Abstract

Purpose

The objective of this phase II study was to evaluate the potential of pharmacokinetic (PK) drug–drug interactions between ramucirumab and irinotecan or its metabolite, SN-38, when administered with folinic acid and 5-fluorouracil (FOLFIRI).

Methods

Patients received intravenous infusions of FOLFIRI and ramucirumab 8 mg/kg on Day 1 of a 2-week cycle. FOLFIRI was administered alone in Cycle 1; ramucirumab followed by FOLFIRI was administered in all subsequent cycles. Blood was collected at regular intervals after infusions in Cycles 1 and 2 to determine irinotecan, SN-38, and ramucirumab concentrations. PK parameters were derived by noncompartmental analysis.

Results

Twenty-nine patients received treatment. The dose-normalized area under the concentration versus time curve from zero to infinity [AUC(0–)] and the maximum observed concentration (C max) of irinotecan and SN-38 were comparable between Cycle 1 (FOLFIRI alone) and Cycle 2 (ramucirumab + FOLFIRI). The ratios of geometric least squares (LS) means for irinotecan were 0.93 (90 % CI 0.83–1.05) for AUC(0–) and 1.04 (90 % CI 0.97–1.12) for C max. The ratios of geometric LS means for SN-38 were 0.95 (90 % CI 0.88–1.04) for AUC(0–) and 0.97 (90 % CI 0.85–1.12) for C max. The most common treatment-emergent adverse events, regardless of grade, were fatigue (19 patients, 65.5 %), diarrhea, (16 patients, 55.2 %), and neutropenia (15 patients, 51.7 %). Grade ≥3 neutropenia was reported in 7 (24.1 %) patients.

Conclusions

There was no PK drug–drug interaction between ramucirumab and irinotecan or its metabolite, SN-38. Ramucirumab with FOLFIRI was well tolerated in this study, with no new safety concerns.

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Acknowledgments

This work was supported by Eli Lilly and Company. Eli Lilly and Company contracted with inVentiv Health Clinical for writing and editorial support, provided by Stacey E. Shehin, PhD, and Noelle Gasco, respectively.

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Correspondence to Ding Wang.

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Conflict of interest

Ding Wang received funding from AbbVie, AstraZeneca, Bayer, Eli Lilly and Company, EMD Serono, Merck, and Novartis. Fadi Braiteh received remuneration from Ambry Genetics, Amgen, AstraZeneca/MedImmune, Bayer, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Foundation Medicine, Heron Therapeutics, Genomic Health, Incyte, INSYS Therapeutics, Ipsen, Merck, Merrimack, Molecular Health, Novartis, Pfizer, Roche/Genentech, and Sanofi, and has a consultant advisory role with Amgen, BIND Therapeutics, BioTheranostics, Caris Life Sciences, Eli Lilly and Company, Foundation Medicine, Incyte, INSYS Therapeutics, Ipsen, Merrimack, Molecular Health, Novartis, Novocure, Pfizer, Roche/Genentech, and Sanofi. James J. Lee has no conflicts to disclose. Crystal S. Denlinger has a consultant/advisory role and received funding from Eli Lilly and Company. Dale R. Shepard has no conflicts to disclose. Archana Chaudhary, Yong Lin, Ling Gao, Christopher Asakiewicz, and Federico Nasroulah are employees of and may own stock in Eli Lilly and Company. Patricia LoRusso has a consultant/advisory role with Alexion, Astellas, Astex, Genentech, and Novartis and received funding from AbbVie, Genentech, and Pfizer.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutions’ ethics committee or institutional review board and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

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Wang, D., Braiteh, F., Lee, J.J. et al. Lack of pharmacokinetic drug–drug interaction between ramucirumab and irinotecan in patients with advanced solid tumors. Cancer Chemother Pharmacol 78, 727–733 (2016). https://doi.org/10.1007/s00280-016-3125-4

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  • DOI: https://doi.org/10.1007/s00280-016-3125-4

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